Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals.

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Drobna Z, Jaspers I, Thomas DJ, Styblo M

Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals.

FASEB J. 2003 Jan;17(1):67-9. Epub 2002 Nov 15.

PubMed ID

12475910 [ View in PubMed

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Abstract

Chronic exposures to inorganic arsenic (iAs) have been linked to increased incidences of various cancers, including cancer of the urinary bladder. Mechanisms by which iAs promotes cancer may include stimulation of activator protein-1 (AP-1) DNA binding through increased expression and/or phosphorylation of the AP-1 constituents. However, the role of methylated metabolites of iAs in AP-1 activation has not been thoroughly examined. In this study, we show that short-time exposures to 0.1-5 microM arsenite (iAsIII) or the methylated trivalent arsenicals methylarsine oxide (MAsIIIO), or iododimethylarsine (DMAsIIII) induce phosphorylation of c-Jun and increase AP-1 DNA binding activity in human bladder epithelial cells. DMAsIIII and especially MAsIIIO are considerably more potent than iAsIII as inducers of c-Jun phosphorylation and AP-1 activation. Phosphorylated c-Jun, JunB, JunD, and Fra-1, but not c-Fos, FosB, or ATF-2, are detected in the AP-1-DNA binding complex in cells exposed to trivalent arsenicals. In cells transiently transfected with an AP-1-dependent promoter-reporter construct, MAsIIIO was more potent than iAsIII in inducing the AP-1-dependent gene transcription. Exposures to trivalent arsenicals induce phosphorylation of extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinases or p38 kinases. These results indicate that an ERK-dependent signal transduction pathway is at least partially responsible for c-Jun phosphorylation and AP-1 activation in UROtsa cells exposed to inorganic or methylated trivalent arsenicals.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arsenic trioxide	Transcription factor AP-1	Protein	Humans	Yes	Inducer	Details